Dual PI3K/Akt Inhibitors Bearing Coumarin-Thiazolidine Pharmacophores as Potential Apoptosis Inducers in MCF-7 Cells.

Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone () and thiazolidin-4-one moieties () were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, , induced remarkable cytotoxicity (IC of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following treatment. Mechanistically, was found to target the PI3K-α/Akt-1 axis, as evidenced by enzyme inhibition assay results reporting significant inhibition of examined enzymes. These findings were confirmed by Western blot results indicating the ability of to repress levels of Cyclin D1, p-PI3K, and p-Akt. Furthermore, docking studies showed that has a binding affinity with the PI3K binding site higher than the original ligands X6K. Our results suggest that has pharmacological potential as a promising anti-cancer compound by the inhibition of the PI3K/Akt axis.